Transplantation of neural stem cells expressing hypoxia-inducible factor-1 alpha (HIF-1 alpha) improves behavioral recovery in a rat stroke model

We explored the possibility that hypoxia-inducible factor-1 alpha (HIF-1 alpha) might contribute to the therapeutic effect of neural stem cell (NSC) transplantation in cerebral ischemia. The relative efficacy of modified NSC to promote behavioral recovery was investigated in a rat model of stroke induced by a transient middle cerebral artery occlusion (MCAO). A recombinant adenovirus (Ad-HIF-1 alpha) was engineered to express HIF-1 alpha. Control NSC infected with control adenovirus (NSC-Ad), recombinant adenovirus Ad-HIF-1 alpha, or NSC infected by Ad-HIF-1 alpha (NSC-Ad-HIF-1 alpha), were used for intraventricular transplantion into rat brain 24 hours after MCAO. Neurological deficits were assessed over 4 weeks using the modified neurological severity scale (NSS) score. Long-term in vivo expression of HIF-1 alpha was demonstrated by Western blotting and immunocytochemistry, and derivatives of nestin-positive transplanted cells contributed to both neuronal (neurofilament-positive) and astroglial (glial fibrillary acidic protein-positive) lineages. All animals showed functional improvement. Improvement was accelerated in animals receiving either NSC-Ad or Ad-HIF-1 alpha, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with NSC-Ad-HIF-1 alpha than for other treated animals. NSC-Ad-HIF-1 alpha cells also increased the number of factor VIII-positive cells in the region of ischemic injury, indicating that HIF-1 alpha expression can promote angiogenesis. Gene-modified NSC expressing HIF-1 alpha have therapeutic potential in ischemic stroke. (C) 2009 Elsevier Ltd. All rights reserved.